This project seeks continuing funding to explore the effects of acute and chronic marijuana use on regional cerebral blood flow (rCBF) and cognitive function. Increased knowledge of marijuana's impact on the human brain has important public health implications since it is the most commonly used illegal drug in the United States (current estimates are that over seven million people use cannabis weekly or more often in the US). Following declines throughout the late 1970s and the 1980s, the prevalence of marijuana use among youth skyrocketed in the early 1990s, and has remained disturbingly high, renewing concerns about potential health risks. The specific aims of the project during the initial funding period were: 1) to study rCBF changes in brain systems mediating cognitive functions that are acutely impaired by smoking MJ in occasional users, and 2) to determine if regular, long-term (i.e., chronic) use alters the acute response of the brain to MJ. We have made a great deal of progress towards achieving these aims. In brief, we found direct effects of MJ that replicated in all four of our initial studies. Smoking marijuana resulted in increased rCBF in an extensive region of the ventral forebrain that included orbital frontal cortex, anterior cingulate, insula, and temporal poles as well as in the cerebellum. Decreased rCBF was consistently found in occipital cortex, and also in auditory cortices, but in a more task-dependent manner. We found that smoking MJ had relatively little effect on behavior, or on the pattern of activation, during an auditory attention task. However, performance on memory tasks was impaired in a group of occasional users, and rCBF was also significantly changed. Chronic users did not show memory impairment after smoking MJ, suggesting that they had developed tolerance to the cognitive effects of the drug, but they did show rCBF differences that differed from the occasional group after both placebo and MJ. The studies proposed here utilize PET with [15O]water and cognitive tasks to assess marijuana's effects on cerebellar-cortical circuitry. We will assess the acute effects of smoking marijuana on cerebellar function in chronic and occasional users during tasks that have been shown to activate the cerebellum in normal volunteers. In addition to standard image subtraction analyses, correlational techniques will assess the "functional connectivity" of the cerebellum with other brain regions. We will also assess cerebellar-cortical circuitry using cognitive tasks that are mediated by ventral forebrain areas that we found to have dramatic increases in rCBF after smoking marijuana. We will also utilize a PET protocol that we recently found to activate reward circuitry to assess the effects of marijuana on these brain regions in chronic and occasional users. Finally, cognitive tasks requiring self-paced timing and other putative cerebellar functions will be used to assess the functional consequences of cerebellar hypoperfusion in chronic users of marijuana.